Amorphous polymeric polyaxial initiators and compliant crystalline copolymers therefrom

ABSTRACT

An absorbable crystalline, monocentric polyaxial copolymer comprising a central carbon or nitrogen atom and at least three axes, each of which includes an amorphous flexible component adjacent and originating from the central atom and a rigid, crystallizable component extending outwardly from the amorphous, flexible component is disclosed along with the use of such copolymer in medical devices which may contain a bioactive agent.

This application claims benefit of provisional application 60/167,998filed Nov. 30, 1999.

BACKGROUND OF THE INVENTION

Since the successful development of crystalline thermoplasticpolyglycolide as an absorbable fiber-forming material, there has been agreat deal of effort directed to the development of new linearfiber-forming polyesters with modulated mechanical properties andabsorption profiles. Such modulation was made possible through theapplication of the concept of chain segmentation or block formation,where linear macromolecular chains comprise different chemical entitieswith a wide range of physicochemical properties, among which is theability to crystallize or impart internal plasticization. Typicalexamples illustrating the use of this strategy are found in U.S. Pat.Nos. 5,554,170, 5,431,679, 5,403,347, 5,236,444, and 5,133,739, wheredifunctional initiators were used to produce linear crystallizablecopolymeric chains having different microstructures.

On the other hand, controlled branching in crystalline, homochainpolymers, such as polyethylene, has been used as a strategy to broadenthe distribution in crystallite size, lower the overall degree incrystallinity and increase compliance (L. Mandelkern, Crystallization ofPolymers, McGraw-Hill Book Company, NY, 1964, p. 105-106). A similar butmore difficult-to-implement approach to achieving such an effect oncrystallinity as alluded to above has been used specifically in theproduction of linear segmented and block heterochain copolymers such as(1) non-absorbable polyether-esters of polybutylene terephthalate andpolytetramethylene oxide [see S. W. Shalaby and H. E. Bair, Chapter 4 ofThermal Characterization of Polymeric Materials (E. A. Turi, Ed.)Academic Press, NY, 1981, p. 402; S. W. Shalaby et al., U.S. Pat. No.4,543,952 (1985)]; (2) block/segmented absorbable copolymers of highmelting crystallizable polyesters such as polyglycolide with amorphouspolyether-ester such as poly-1,5-dioxepane-2-one (see A. Kafrawy et al.,U.S. Pat. No. 4,470,416 (1984)); and (3) block/segmented absorbablecopolyesters of crystallizable and non-crystallizable components ascited in U.S. Pat. Nos. 5,554,170, 5,431,679, 5,403,347, 5,236,444, and5,133,739. However, the use of a combination of controlled branching(polyaxial chain geometry) and chain segmentation or block formation ofthe individual branches to produce absorbable polymers with tailoredproperties cannot be found in the prior art. This and recognized needsfor absorbable polymers having unique combinations of crystallinity andhigh compliance that can be melt-processed into high strength fibers andfilms with relatively brief absorption profiles as compared to theirhomopolymeric crystalline analogs provided an incentive to explore anovel approach to the design of macromolecular chains to fulfill suchneeds. Meanwhile, initiation of ring-opening polymerization with organiccompounds having three or four functional groups have been used as ameans to produce crosslinked elastomeric absorbable systems as in theexamples and claims of U.S. Pat. No. 5,644,002. Contrary to this priorart and in concert with the recognized needs for novel crystallizable,melt-processable materials, the present invention deals with thesynthesis and use of polyaxial initiators with three or more functionalgroups to produce crystallizable materials with melting temperaturesabove 100° C., which can be melt-processed into highly compliantabsorbable films and fibers.

SUMMARY OF THE INVENTION

In one aspect the present invention is directed to an absorbable,crystalline, monocentric, polyaxial copolymer which includes a centralatom which is carbon or nitrogen and at least three axes originating andextending outwardly from the central atom, with axis including anamorphous, flexible component adjacent to and originating from thecentral atom, the amorphous component being formed of repeat unitsderived from at least one cyclic monomer, either a carbonate or alactone, and a rigid, crystallizable component extending outwardly fromthe amorphous, flexible component, the crystallizable component beingformed of repeat units derived from at least one lactone.

In another aspect the present invention is directed to an absorbable,monocentric, polyaxial copolymer made by a process which includes thesteps of:

a) providing a monomeric initiator which is an organic compound selectedfrom the group consisting of tri-functional organic compounds andtetra-functional organic compounds;

b) providing a catalyst based on a multivalent metal;

c) reacting at least one cyclic comonomer selected from the groupconsisting essentially of carbonates and lactones with the monomericinitiator in the presence of the catalyst such that an amorphouspolymeric, polyaxial initiator is formed by ring-opening polymerizationof the at least one cyclic comonomer; and

d) reacting the amorphous, polymeric polyaxial initiator with at leastone lactone comprising a member selected from the group consisting ofglycolide, lactide, ρ-dioxanone, and combinations thereof.

DESCRIPTION OF PREFERRED EMBODIMENTS

This invention deals with absorbable, polyaxial, monocentric,crystallizable, polymeric molecules with non-crystallizable, flexiblecomponents of the chain at the core and rigid, crystallizable segmentsat the chain terminals. More specifically, the present invention isdirected to the design of amorphous polymeric polyaxial initiators withbranches originating from one polyfunctional organic compound so as toextend along more than two coordinates and their copolymerization withcyclic monomers to produce compliant, crystalline film- andfiber-forming absorbable materials. The absorbable copolymeric materialsof this invention comprise at least 30 percent, and preferably 65percent, by weight, of a crystallizable component which is madeprimarily of glycolide-derived or 1-lactide-derived sequences, andexhibit first and second order transitions below 222° C. and below 42°C., respectively, and undergo complete dissociation into water-solubleby-products in less than 180 days and preferably 120 days when incubatedin a phosphate buffer at 37° C. and pH 7.4 or implanted in livingtissues.

The amorphous polymeric, polyaxial initiators (PPIs) used in thisinvention to produce crystalline absorbable copolymeric materials can bemade by reacting a cyclic monomer or a mixture of cyclic monomers suchas trimethylene carbonate, ε-caprolactone, and 1,5-dioxapane-2-one inthe presence of an organometallic catalyst with one or more polyhydroxy,polyamino, or hydroxyamino compound having more than three reactiveamines and/or hydroxyl groups. Typical examples of the latter compoundsare glycerol, ethane-trimethylol, propane-trimethylol, pentaerythritol,a partially alkylated cyclodextrin, triethanolamine,N-2-aminoethyl-1,3-propanediamine, 3-amino-5-hydroxy pyrazole, and4-amino-6-ydroxy-2-mercapto-pyrimidine.

The crystalline copolymers of the present invention are so designed to(1) have the PPI devoid of any discernable level of crystallinity; (2)have the PPI component function as a flexible spacer of a terminallyplaced, rigid, crystallizable component derived primarily from glycolideso as to allow for facile molecular entanglement to createpseudo-crosslinks, which in turn, maximize the interfacing of theamorphous and crystalline fractions of the copolymer leading to highcompliance without compromising tensile strength; (3) maximize theincorporation of the hydrolytically labile glycolate linkage in thecopolymer without compromising the sought high compliance-this isachieved by directing the polyglycolide segments to grow on multipleactive sites of the polymeric initiator and thus limiting the length ofthe crystallizable chain segments; (4) have a broad crystallizationwindow featuring maximum nucleation sites and slow crystallite growththat in turn assists in securing a highly controlled post-processing anddevelopment of mechanical properties—this is achieved by allowing thecrystallizable components to entangle effectively withnon-crystallizable components leading to high affinity for nucleation,high pre-crystallization viscosity, slow chain motion, and low rate ofcrystallization; (5) force the polymer to form less perfect crystalliteswith broad size distribution and lower their melting temperature ascompared to their homopolymeric crystalline analogs to aidmelt-processing—this is achieved by limiting the length of thecrystallizable segments of the copolymeric chain as discussed earlier;(6) allow for incorporating basic moieties in the PPI which can affectautocatalytic hydrolysis of the entire system which in turn acceleratesthe absorption rate; and (7) allow the polymer chain to associate so asto allow for endothermic thermal events that can be related to tensiletoughness similar to that detected in PET relative to the so-calledmiddle endothermic peak (MEP) (S. W. Shalaby, Chapter 3 of ThermalCharacterization of Polymeric Materials, Academic press, NY, 1981, p.330).

As an example, the crystalline copolymeric materials of the presentinvention may be prepared as follows, although as noted above, othermonomers are also within the scope of the present invention. Theamorphous polymeric polyaxial initiator is formed by a preliminarypolymerization of a mixture of ε-caprolactone and trimethylene carbonatein the presence of trimethylol-propane and a catalytic amount ofstannous octoate, using standard ring-opening polymerization conditionswhich entail heating the stirred reactants in nitrogen atmosphere at atemperature exceeding 110° C. until substantial or complete conversionof the monomers is realized. This can be followed by adding apredetermined amount of glycolide. Following the dissolution of theglycolide in the reaction mixture, the temperature is raised above 150°C. to allow the glycolide to copolymerize with the polyaxial initiator.When practically all the glycolide is allowed to react, the resultingcopolymer is cooled to 25° C. After removing the polymer from thereaction kettle and grinding, trace amounts of unreacted monomer areremoved by heating under reduced pressure. The ground polymer can thenbe extruded and pelletized prior to its conversion to fibers or films byconventional melt-processing methods. At the appropriate stage ofpolymerization and product purification, traditional analytical methods,such as gel-permeation chromatography (GPC), solution viscosity,differential scanning calorimetry (DSC), nuclear magnetic resonance(NMR), and infrared spectroscopy (IR) are used to monitor or determine(directly or indirectly) the extent of monomer conversion, molecularweight, thermal transitions (melting temperature, Tm, and glasstransition temperature, Tg), chain microstructure, and chemical entity,respectively.

Another aspect of this invention deals with end-grafting a PPI withε-caprolactone or 1-lactide, and preferably in the presence of a minoramount of a second monomer, to produce absorbable crystalline polymersfor use as bone sealants or barrier membranes, respectively.

Films made by compression molding of the copolymers described in theexamples set forth below are evaluated for (1) tensile strength; (2) invitro breaking strength retention and mass loss during incubation in aphosphate buffer at 37° C. and pH 7.4; (3) in vivo breaking strengthretention using a rat model where strips of the films are implantedsubcutaneously for 1 to 6 weeks and individual lengths are explantedperiodically to determine percent of retained breaking strength; and (4)in vivo absorption (in terms of mass loss) using a rat model where afilm strip, inserted in a sealed polyethylene terephthalate (PET) wovenbag, is placed in the peritoneum for 6, 8, 10, 12 and 14 weeks. At theend of each period, the PET bag is removed and the residual mass of thestrips is removed, rinsed with water, dried, and its weight isdetermined.

Specifically, an important aspect of this invention is the production ofcompliant absorbable films with modulated absorption and strength lossprofiles to allow their use in a wide range of applications as vasculardevices or components therefor; more specifically is the use of thesedevices in sealing punctured blood vessels.

In another aspect, this invention is directed to the use of the polymersdescribed herein for the production of extruded or molded films for usein barrier systems to prevent post-surgical adhesion or compliantcovers, sealants, or barriers for bums and ulcers as well ascompromised/damaged tissue. The aforementioned articles may also containone or more bioactive agent to augment or accelerate their functions. Inanother aspect, this invention is directed to melt-processed films foruse to patch mechanically compromised blood vessels. In another aspect,this invention is directed to the use of the polymer described herein asa coating for intravascular devices such as catheters and stents. Inanother aspect, this invention is directed to the application of thepolymers described herein in the production of extruded catheters foruse as transient conduits and microcellular foams with continuous porousstructure for use in tissue engineering and guiding the growth of bloodvessels and nerve ends. Another aspect of this invention is directed tothe use of the polymers described herein to produce injection moldedarticles for use as barriers, or plugs, to aid the function of certainbiomedical devices used in soft and hard tissues and which can beemployed in repairing, augmenting, substituting or redirecting/assistingthe functions of several types of tissues including bone, cartilage, andlung as well as vascular tissues and components of the gastrointestinaland urinogenital systems. In another aspect, this invention is directedto the use of polymers described herein to produce compliant, melt-blownfabrics and monofilament sutures with modulated absorption and strengthretention profiles.

In one aspect of this invention, the subject copolymers are converted todifferent forms of absorbable stents, such as those used (1) as anintraluminal device for sutureless gastrointestinal suturelessanastomosis; (2) in laparoscopic replacement of urinary tract segments;(3) as an intraluminal device for artery welding; (4) in the treatmentof urethral lesions; (5) as a tracheal airway; (6) in the treatment ofrecurrent urethral strictures; (7) for vasectomy reversal; (8) in thetreatment of tracheal stenoses in children; (9) for vasovasostomy; (10)for end-to-end ureterostomy; and (11) as biliary devices.

In another aspect of this invention, the subject copolymers areconverted to a highly compliant, expandable tubular mantle, sleeve orcover that is placed tightly outside an expandable metallic or polymericstent so that under concentric irreversible expansion at the desiredsite of a treated biological conduit, such as a blood vessel or aurethra, both components will simultaneously expand and the mantleprovides a barrier between the inner wall of the conduit and the outerwall of the stent. In another aspect of this invention, the subjectcopolymers are used as a stretchable matrix of a fiber-reinforced cover,sleeve, or mantle for a stent, wherein the fiber reinforcement is in theform of spirally coiled yarn (with and without crimping) woven, knitted,or braided construct. In another aspect of this invention, the stentmantle, or cover, is designed to serve a controlled release matrix ofbioactive agents such as those used (1) for inhibiting neointimaformation as exemplified by hirudin and the prostacyclic analogue,iloprost; (2) for inhibiting platelet aggregation and thrombosis; (3)for reducing intraluminal and particular intravascular inflammation asexemplified by dexamethasone and non-steroidal inflammatory drugs, suchas naproxen; and (4) for suppressing the restenosis.

One aspect of this invention deals with the conversion of the subjectcopolymers into molded devices or components of devices used as ahemostatic puncture closure device after coronary angioplasty.

It is further within the scope of this invention to incorporate one ormore medico-surgically useful substances into the copolymers and devicessubject of this invention. Typical examples of these substances arethose capable of (1) minimizing or preventing platelet adhesion to thesurface of vascular grafts; (2) rendering anti-inflammatory functions;(3) blocking incidents leading to hyperplasia as in the case ofsynthetic vascular grafts; (4) aiding endothelialization of syntheticvascular grafts; (5) preventing smooth muscle cell migration to thelumen of synthetic vascular grafts; and (6) accelerating guided tissueingrowth in fully or partially absorbable scaffolds used in vasculartissue engineering.

In order that those skilled in the art may be better able to practicethe present invention, the following illustrations of the preparation oftypical crystalline copolymers are provided.

EXAMPLE 1 Synthesis of 20/25 (molar) ε-Caprolactone/TrimethyleneCarbonate Copolymer as a Tri-axial Initiator and Reaction with 55Relative Molar Parts of Glycolide

An initial charge consisted of 142.4 grams (1.249 moles) ε-caprolactone,159.4 grams (1.563 moles) trimethylene carbonate, 1.666 grams (1.24×10⁻²moles) trimethylol-propane, and 1.0 ml (2.03×10⁻⁴ moles) of a 0.203Msolution of stannous octoate catalyst in toluene after flame drying thereaction apparatus. The reaction apparatus was a 1 L stainless steelkettle with 3-neck glass lid equipped with an overhead mechanicalstirring unit, vacuum adapter, and two 90° connectors for an argoninlet.

The apparatus and its contents were heated to 50° C. under vacuum with ahigh temperature oil bath. Upon complete melting of the contents after30 minutes, the system was purged with argon, stirring initiated at 32rpm, and the temperature set to 150° C. After 4 hours at 150° C., theviscosity of the polyaxial polymeric initiator (PPI) had increased andthe temperature of the bath was reduced to 110° C. Upon reaching 110°C., 398.5 grams (3.435 moles) of glycolide were added to the system.When the glycolide had completely melted and mixed into the polyaxialpolymeric initiator, the temperature was increased to 180° C. andstirring was stopped. The reaction was allowed to continue for 2 hoursbefore cooling the system to 50° C. and maintaining the heat overnight.The polymer was isolated, ground, dried, extruded and redried asdescribed below in Example 5.

The extrudate was characterized as follows: The inherent viscosity usinghexafluoro-isopropyl alcohol (HFIP) as a solvent was 0.97 dL/g. Themelting temperature and heat of fusion, as determined by differentialscanning calorimetry (using initial heating thermogram), were 215° C.and 40.8 J/g, respectively.

EXAMPLE 2 Synthesis of 25/30 (molar) ε-Caprolactone/TrimethyleneCarbonate Copolymer as a Tri-axial Initiator and Reaction with 45Relative Molar Parts of Glycolide

An initial charge consisted of 122.8 grams (1.077 moles) ε-caprolactone,131.9 grams (1.292 moles) trimethylene carbonate, 1.928 grams (1.44×10⁻²moles) trimethylol-propane, and 1.0 ml (8.62×10⁻⁵ moles) of a 0.086Msolution of stannous octoate catalyst in toluene after flame drying thereaction apparatus. The reaction apparatus was a 1 L stainless steelkettle with 3-neck glass lid equipped with an overhead mechanicalstirring unit, vacuum adapter, and two 90° connectors for an argoninlet.

The apparatus and its contents were then heated to 65° C. under vacuumwith a high temperature oil bath. After 30 minutes, with the contentscompletely melted, the system was purged with argon, stirring initiatedat 34 rpm, and the temperature set to 140° C. After 3 hours at 140° C.,the temperature was raised to 150° C. for 1 hour and then reduced backto 140° C. At this point, 225.0 grams (1.940 moles) of glycolide wereadded to the system while rapidly stirring. When the glycolide hadcompletely melted and mixed into the polyaxial polymeric initiator, thetemperature was increased to 180° C. and stirring was stopped. Thereaction was allowed to continue for 2 hours before cooling the systemto room temperature overnight. The polymer was isolated, ground, dried,extruded, and redried as described in Example 5.

Characterization of the extrudate was conducted as follows: The inherentviscosity using HFIP as a solvent was 0.93 dL/g. The melting temperatureand heat of fusion, as measured by differential scanning calorimetry(DSC using initial heating thermogram), were 196° C. and 32.1 J/g,respectively.

EXAMPLE 3 Synthesis of 20/25/3 (molar) ε-Caprolactone/TrimethyleneCarbonate/Glycolide Copolymer as a Tri-axial Initiator and Reaction with52 Relative Molar Parts of Glycolide

An initial charge consisted of 101.6 grams (0.891 moles) ε-caprolactone,113.5 grams (1.113 moles) trimethylene carbonate, 15.5 grams ofglycolide (0.134 moles), 1.996 grams (1.49×10-2 moles)trimethylol-propane, and 1.0 ml (1.28×10⁻⁴ moles) of a 0.128M solutionof stannous octoate catalyst in toluene after flame drying the reactionapparatus. The reaction apparatus was a 1 L stainless steel kettle with3-neck glass lid equipped, an overhead mechanical stirring unit, vacuumadapter, and two 90° connectors for an argon inlet.

The apparatus and its contents were then heated to 85° C. under vacuumwith a high temperature oil bath. After 30 minutes, with the contentscompletely melted, the system was purged with argon, stirring initiatedat 34 rpm, and the temperature set to 140° C. After 4 hours at 140° C.,268.8 grams (2.317 moles) of glycolide were added to the system whilerapidly stirring. When the glycolide had completely melted and mixedinto the polyaxial polymeric initiator, the temperature was increased to180° C. and stirring was stopped. The reaction was allowed to continuefor 2 hours before cooling the system to room temperature overnight. Thepolymer was isolated, ground, dried, extruded and redried as in Example5.

The extrudate was characterized as follows: The inherent viscosity usingHFIP as a solvent was 0.89 dL/g. The melting temperature and heat offusion, as measured by differential scanning calorimetry (DSC usinginitial heating thermogram), were 212° C. and 34 J/g, respectively.

EXAMPLE 4 Synthesis of 20/25/3 (molar)ε-Caprolactone/Trimethylene-Carbonate/Glycolide Copolymer as a Tri-axialInitiator and Reaction with 52 Relative Molar Parts of Glycolide

Glycolide (18.6 g, 0.1603 mole), TMC (136.7 g, 1.340 mole),ε-caprolactone (122.0 g, 1.070 mole), trimethylolpropane (2.403 g,0.01791 mole) and stannous octoate catalyst (0.2M in toluene, 764 μL,0.1528 mmol) were added under dry nitrogen conditions to a 1.0 literstainless steel reaction kettle equipped with a glass top and amechanical stirrer. The reactants were melted at 85° C. and the systemwas evacuated with vacuum. The system was purged with dry nitrogen andthe melt was heated to 160° C. with stirring at 30 rpm. Samples of theprepolymer melt were taken periodically and analyzed for monomer contentusing GPC. Once the monomer content of the melt was found to benegligible, glycolide (322.5 g, 2.780 mole) was added with rapidstirring. The stir rate was lowered to 30 rpm after the contents werewell mixed. The melt was heated to 180° C. Stirring was stopped uponsolidification of the polymer. The polymer was heated for 2 hours at180° C. after solidification. The resulting polymer was cooled to roomtemperature, quenched in liquid nitrogen, isolated, and dried undervacuum. The polymer was isolated, ground, redried, and extruded asdescribed in Example 5. The extrudate was characterized by NMR and IRfor identity and DSC (using initial heating thermogram) for thermaltransition (T_(m)=208° C., ΔH=28.0 J/g) and solution viscosity inhexafluoroisopropyl alcohol (η=0.92 dL/g).

EXAMPLE 5 Size Reduction and Extrusion of Polymers of Examples 1 through4

The polymer was quenched with liquid nitrogen and mechanically ground.The ground polymer was dried under vacuum at 25° C. for two hours, at40° C. for two hours, and at 80° C. for four hours. The polymer was meltextruded at 225° C. to 235° C. using a ½ inch extruder equipped with a0.094 in die. The resulting filaments were water cooled. The averagefilament diameter was 2.4 mm. The filament was dried at 40° C. and 80°C. under vacuum for eight and four hours, respectively.

EXAMPLE 6 Compression-molding of Polymers from Examples 3 and 4 to aSealing Device for a Punctured Blood Vessel and Its Packaging

The compression molding process entailed exposing the polymer to anelevated temperature between two mold halves. When temperature of themold halves exceeded the polymer melting temperature, pressure wasapplied to the mold and the material was allowed to flow into apredefined cavity of the mold. The mold was then cooled to roomtemperature before it was opened and the newly shaped polymer wasremoved.

The full molding cycle can be described as: (1) Drying—typical:temperature 80° C. during 2 hours; (2) Pre-heating, temperatureincrease—typical: pressure 5,000N, temperature from room temperature upto 200° C.; (3) Forming, constant temperature under highpressure—typical: pressure 50,000N, temperature 200° C.; (4) Cooling,temperature decrease under high pressure—typical: pressure 50,000N,temperature from 200° C. down to 50° C.; (5) Mold opening; (6)Annealing—typical: temperature 80° C. during 2 hours; and (7)Packaging—typically the device was removed from the mold and packagedunder vacuum under a protective gas environment.

EXAMPLE 7 Synthesis of 13.3/17.7/2 (molar) Caprolactone/TrimethyleneCarbonate/ Glycolide Copolymer as a Tri-axial Initiator and Reactionwith Relative 67 Molar Parts of Glycolide

Glycolide (10.4 g, 0.090 mole), TMC (76.5 g, 0.750 mole), ε-caprolactone(68.4 g, 0.600 mole), trimethylolpropane (1.995 g, .01487 mole) andstannous octoate catalyst (0.2M in toluene, 637 μL, 0.1274 mmole) wereadded under dry nitrogen conditions to a 1.0 liter stainless steelreaction kettle equipped with a glass top and a mechanical stirrer. Thereactants were melted at 85° C. and the system was evacuated withvacuum. The system was purged with dry nitrogen and the melt was heatedto 160° C. with stirring at 30 rpm. Samples of the prepolymer melt weretaken periodically and analyzed for monomer content using GPC. Once themonomer content of the melt was found to be negligible, glycolide (344.5g, 2.970 mole) was added with rapid stirring. The stir rate was loweredto 30 rpm after the contents were well mixed. The melt was heated to180° C. Stirring was stopped upon solidification of the polymer. Thepolymer was heated for 2 hours at 180° C. after solidification. Theresulting polymer was cooled to room temperature, quenched in liquidnitrogen, isolated, and dried under vacuum. The polymer wascharacterized by NMR and IR (for identity), DSC thermal transition(T_(m)=215.7) and solution viscosity in hexafluoroisopropyl alcohol(η−0.95 dL/g).

EXAMPLE 8 Synthesis of 13.6/17.0/2.0 (molar) ε-Caprolactone/TrimethyleneCarbonate/Glycolide Copolymer as a Basic Tri-axial Initiator andReaction with Relative 67.4 Molar Parts of Glycolide and TrimethyleneCarbonate

Glycolide (3.1 g, 0.0267 mole), TMC (23.0 g, 0.2255 mole),ε-caprolactone (20.5 g, 0.1798 mole), triethanolamine (0.6775 g, 4.55mmole) and stannous octoate catalyst (0.2M in toluene, 519 μL, 0.1038mmole) were added under dry nitrogen conditions to a 0.5 Liter stainlesssteel reaction kettle equipped with a glass top and a mechanicalstirrer. The reactants were melted at 85° C. and the system wasevacuated with vacuum. The system was purged with dry nitrogen and themelt was heated to 160° C. with stirring at 30 rpm. Samples of theprepolymer melt were taken periodically and analyzed for monomer contentusing GPC. Once the monomer content of the melt was found to benegligible, glycolide (103.4 g, 0.8914 mole) was added with rapidstirring. The stir rate was lowered to 30 rpm after the contents werewell mixed. The melt was heated to 180° C. Stirring was stopped uponsolidification of the polymer. The polymer was heated for 2 hours at180° C. after solidification. The resulting polymer was cooled to roomtemperature, quenched in liquid nitrogen, isolated, and dried undervacuum. The polymer was characterized for identity and composition (IRand NMR, respectively) and thermal transition by DSC (T_(m)220° C.) andmolecular weight by solution viscometry (η=0.80 in hexafluoroisopropylalcohol).

EXAMPLE 9 Synthesis of 13.6/17.0/2.0 (molar) ε-Caprolactone/TrimethyleneCarbonate/Glycolide Copolymer as a Basic Tri-axial Initiator andReaction with Relative 67.4 Molar Parts of Glycolide

The two-step polymerization was conducted as in Example 8 with theexception of using 0.6915 g triethanolamine and 693 μl of stannousoctanoate solution. The final polymer was isolated and characterized asin Example 8 and it was shown to have a T_(m)=221° C. and inherentviscosity (in HFIP)=0.82.

EXAMPLE 10 Synthesis of 13.3/17.7/2 (molar) ε-Caprolactone/TrimethyleneCarbonate/Glycolide Copolymer as a Tetra-axial Initiator and Reactionwith Relative 67 Molar Parts of Glycolide

Glycolide (3.1 g, 0.0267 mole), TMC (23.0 g, 0.2255 mole),ε-caprolactone (20.5 g, 0.1796 mole), pentaerythritol (0.600 g., 0.0044mole) and stannous octoate catalyst (0.2 M in toluene, 193 μl, 0.0386mmol) were placed under dry nitrogen conditions to a 0.5 L stainlesssteel reaction kettle equipped with a glass top and a mechanicalstirrer. The polymerization charge was dried at 25° C. and 40° C. underreduced pressure for 60 and 30 minutes, respectively. The reactants werethen melted at 85° C. and the system was purged with dry nitrogen. Themelt was heated to 160° C. with stirring at 30 rpm. Samples of theprepolymer melt were taken periodically and analyzed for monomer contentusing GPC (gel permeation chromatography). Once the monomer content ofthe polymer melt was found to be negligible, glycolide (103.4 g., 0.8914mole) was added with rapid stirring that is more than 40 rpm. Thestirring rate was then lowered to 30 rpm after the contents were wellmixed. The reactants were heated to 180° C. Stirring was stopped uponsolidification of the polymer. The polymer was heated for 2 hours at180° C. after solidification. The resulting polymer was cooled to roomtemperature, quenched in liquid nitrogen, isolated, and dried at 25° C.and then 40° C. under reduced pressure.

The final polymer was isolated and characterized as in Example 8 and itwas shown to have a T_(m)=219° C. and inherent viscosity (in HFIP)=0.98.

EXAMPLE 11 Size Reduction and Extrusion of Polymer from Examples 7through 10

The polymer was quenched with liquid nitrogen and mechanically ground.The ground polymer was dried under vacuum at 25° C. for two hours, at40° C. for two hours, and at 80° C. for four hours. The polymer was meltextruded at 235° C. to 245° C. using a ½ inch extruder equipped with a0.094 in die. The resulting monofilament was quenched in an ice-waterbath before winding. The monofilament was dried at 40° C. and undervacuum for four hours before orientation.

EXAMPLE 12 Orientation of Melt-spun Monofilaments

Polymers of Examples 7 through 10 that have been extruded as describedin Example 11 were oriented by two-stage drawing into monofilamentsutures. Prior to drawing Example 7, monofilaments were pre-tensionedand annealed. The drawing was conducted at 90-100° C. in the first stageand 100-130° C. in the second stage. The overall draw ratio variedbetween 3.73× and 4.6×. A number of monofilaments were relaxed at 70° C.for 15 minutes to reduce their free shrinkage. Properties of theoriented monofilaments are summarized in Table I.

TABLE I Drawing Conditions and Fiber Properties of Polymers fromExamples 7 through 9 Origin of Draw Pre-Draw Post-Draw Free StraightModu- Elonga- Extruded Fiber Draw Temp. Annealing Relaxation ShrinkageDiameter Strength lus tion Polymer Number Ratio (S1/S2) (min/° C.) (%)(%) (mil) (Kpsi) (Kpsi) (%) Example 7 7F-1 3.73X 95/130 35/65 — 4.4 13.475 444 22 7 7F-2 3.73X 95/130 35/65 2.3 1.8 15.1 53 182 36 7 7F-3 4.14X95/120 30/65 — 4.2 10.2 66 434 19 7 7F-4 4.14X 95/120 30/65 3   1.5 11.061 257 31 8 8F-1 4.50X 100/120  — — 3.1 10.2 71 195 26 9 9F-1 4.43X100/130  — — 2.1 10.6 72 230 27 10 10F-1  4.60X 95/120 — — 2.4 12.6 57158 25

EXAMPLE 13 Sterilization of Monofilament Sutures and Evaluation of TheirIn Vitro Breaking Strength Retention

Monofilament sutures Numbers 8F-1 and 9F-1 described in Table I wereradiochemically sterilized in hermetically sealed foil packages thathave been pre-purged with dry nitrogen gas, using 5 and 7.5 KGy of gammaradiation. The radiochemical sterilization process entails the use of200-400 mg of Delrin (poly-formaldehyde) film as package inserts for thecontrolled release, radiolytically, of formaldehyde gas as describedearlier by Correa et al., [Sixth World Biomaterials Congress, Trans Soc.Biomat., II, 992 (2000)]. The sterile monofilament sutures wereincubated in a phosphate buffer at 37° C. and pH 7.4 to determine theirbreaking strength retention profile as absorbable sutures. Using thebreaking strength data of non-sterile sutures (Table I), the breakingstrength retention data of sterile sutures were calculated. A summary ofthese data are given in Table II. These data indicate all suturesretained measurable strength at two weeks in the buffer solution.

TABLE II Tensile Properties and In Vitro Breaking Strength Retention(BSR) of Radiochemically Sterilized Monofilament Sutures Suture Number9F-1 8F-1 Sterilization Dose (KGy) 5 7.5 5 7.5 Post-irradiation TensileProperties Tensile Strength (Kpsi) 66 68 67 65 Modulus (Kpsi) 266 254269 263 Elongation (Kpsi) 30 35 31 30 BSR, % at Week 1 70 57 82 72 Week2 24 22 18 17

Although the present invention has been described in connection with thepreferred embodiments, it is to be understood that modifications andvariations may be utilized without departing from the principles andscope of the invention, as those skilled in the art will readilyunderstand. Accordingly, such modifications may be practiced within thescope of the following claims. Moreover, Applicants hereby disclose allsubranges of all ranges disclosed herein. These subranges are alsouseful in carrying out the present invention.

What is claimed is:
 1. An absorbable, crystalline, monocentric,polyaxial copolymer comprising: a central atom selected from the groupconsisting of carbon and nitrogen; and at least three axes originatingand extending outwardly from the central atom, each axis comprising: anamorphous, flexible component adjacent to and originating from thecentral atom, the amorphous component comprising repeat units derivedfrom at least one cyclic monomer selected from the group consistingessentially of carbonates and lactones; and a rigid, crystallizablecomponent extending outwardly from the amorphous, flexible component,the crystallizable component comprising repeat units derived from atleast one lactone.
 2. The polyaxial copolymer set forth in claim 1wherein the amorphous component comprises repeat units derived fromε-caprolactone.
 3. The polyaxial copolymer set forth in claim 1 whereinthe amorphous component comprises repeat units derived from trimethylenecarbonate.
 4. The polyaxial copolymer set forth in claim 2 wherein theamorphous component further comprises repeat units derived fromtrimethylene carbonate.
 5. The polyaxial copolymer set forth in claim 2wherein the amorphous component further comprises repeat units derivedfrom glycolide.
 6. The polyaxial copolymer set forth in claim 3 whereinthe amorphous component further comprises repeat units derived fromglycolide.
 7. The polyaxial copolymer set forth in claim 4 wherein theamorphous component further comprises repeat units derived fromglycolide.
 8. The polyaxial copolymer set forth in claim 1 wherein thecrystallizable component comprises repeat units derived from glycolide.9. The polyaxial copolymer set forth in claim 8 wherein thecrystallizable component further comprises repeat units derived from asecond comonomer selected from the group consisting of trimethylenecarbonate, ε-caprolactone, l-lactide, ρ-dioxanone, and 1,5dioxepane-2-one.
 10. The polyaxial copolymer set forth in claim 1wherein said copolymer comprises a suture.
 11. The polyaxial copolymerset forth in claim 1 wherein said copolymer comprises a molded articlefor sealing punctured blood vessels.
 12. The polyaxial copolymer setforth in claim 1 wherein said copolymer comprises a compliant cover fora stent.
 13. An absorbable, monocentric, polyaxial copolymer made by theprocess comprising the steps of: e) providing a monomeric initiatorcomprising an organic compound selected from the group consisting oftri-functional organic compounds and tetra-functional organic compounds;f) providing a catalyst comprising a multivalent metal; g) reacting atleast one cyclic comonomer selected from the group consistingessentially of carbonates and lactones with the monomeric initiator inthe presence of the catalyst such that an amorphous polymeric, polyaxialinitiator is formed by ring-opening polymerization of the at least onecyclic comonomer; and h) reacting the amorphous, polymeric polyaxialinitiator with at least one lactone comprising a member selected fromthe group consisting of glycolide, lactide, ρ-dioxanone, andcombinations thereof.
 14. The polyaxial copolymer set forth in claim 13wherein the at least one cyclic comonomer comprises ε-caprolactone. 15.The polyaxial copolymer set forth in claim 13 wherein the at least onecyclic comonomer comprises trimethylene carbonate.
 16. The polyaxialcopolymer set forth in claim 14 wherein the at least one cycliccomonomer further comprises trimethylene carbonate.
 17. The polyaxialcopolymer set forth in claim 14 wherein the at least one cycliccomonomer further comprises glycolide.
 18. The polyaxial copolymer setforth in claim 15 wherein the at least one cyclic comonomer furthercomprises glycolide.
 19. The polyaxial copolymer set forth in claim 16wherein the at least one cyclic comonomer further comprises glycolide.20. The polyaxial copolymer set forth in claim 13 wherein the step ofreacting the amorphous, polymeric polyaxial initiator with at least onelactone further comprises reaction with a second comonomer selected fromthe group consisting of trimethylene carbonate, ε-caprolactone, and 1,5dioxepane-2-one.